Ovarian cancer has a poor prognosis because it is often diagnosed at an advanced stage. Screening average risk women is not recommended as randomized trials found no decrease in mortality. Screening high risk women with annual CA-125 and transvaginal ultrasound may detect some early stage cancers but also has many false positives. The UKCTOCS trial found the multimodal screening strategy of combining CA-125 interpreted through ROCA and ultrasound had higher sensitivity and positive predictive value than ultrasound alone. Final mortality data from this large trial is still pending in 2015.

1. SCREENING FOR OVARIAN
CANCER.
HASSAN LATIFAH
GYNECOLOGIC ONCOLOGIST
KFSH&RC – JEDDAH May 2015

2. Ovarian cancer – the troublesome female
genital cancer.
Background
 Ovarian cancer has a poor survival rate because it is often diagnosed at
an advanced stage.
 About 75% are in FIGO stage 3 and 4 at the time of diagnosis.
 5-year survival is over 90 percent for the minority of women with stage I
disease, 25% for those with distant metastasis.
 Survival rate is almost identical for all gynaecological cancers
stage‐by‐stage.
 In order to improve survival the malignancy should be detected and
treated at an earlier stage.

3. RISKS AND BENEFITS OF SCREENING
 The potential benefit of screening is its ability
to identify ovarian cancer at a more localized
and curable stage, leading to reduced
mortality from the disease.
 The risk is that a positive screening test for
ovarian cancer most often is followed by
surgery (either laparoscopy or laparotomy).

4. Screening tests
 PPV : 10% ie no more than 9 healthy
women with false positive screens would
undergo unnecessary procedures for each
case of ovarian cancer detected.
 A screening program that targets all women
over age 50 would require a test with a
specificity of at least 99.6 % , a sensitivity of
at least 80 % to achieve a PPV of 10%,

5. Screening tests:Tumor markers
 CA-125 :
- raised in 50% of women with early stage ovarian cancer
and over 80% of women with advanced disease.
 Limited specificity :
- raised in 1 % of healthy women , fluctuates during
menstrual cycle .
- Endometriosis – Fibroids-Cirrhosis-PID
- Cancers of the endometrium , breast ,lung
and Pancreas.
- Pleural or peritoneal fluid due to any cause.

6. Screening tests : CA-125
 Annual CA 125 measurements alone lack
sufficient specificity for use in an average-risk
population of postmenopausal women.
 Its use in premenopausal women carries a
substantially higher likelihood of false-
positive tests due to menstrual cycle
variations and the prevalence of benign
gynecologic conditions.

7. Screening tests: CA-125
 Three large screening studies have shown that
the specificity of a single CA 125 level for
detection of ovarian neoplasms in
postmenopausal women ranged from 98.6 to
99.4 percent, resulting in an unacceptably low
positive predictive value of 3 percent.
.Elevated serum CA 125 levels prior to diagnosis of ovarian neoplasia: relevance for early detection of
ovarian cancer.Zurawski VRJr et al IntJ Cancer. 1988;42(5):677.
.Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and
ultrasonography. AUJacobs I et al BMJ. 1993;306(6884):1030. .

8. Screening tests: CA-125
 In the ovarian component of PLCO, 78,237 healthy women between
55 and 74 years of age were randomly assigned to screening and
control groups.
 39,115 women were assigned to screening with annual CA 125 and
annual transvaginal ultrasound.
 Data from the baseline prevalence screen in 28,816 women found an
abnormal CA 125 in 436 women (1.5 percent)
 The positive predictive value for invasive cancer was 3.7 percent .

9. Pelvic ultrasonography
 UKCTOCS the largest study to date, 48,230
women aged 50 to 74 years were randomly
assigned to screening with annualTVUS as one
arm of a randomized trial comparing multimodal
screening (MMS),TVUS, and no screening.
 The sensitivity, specificity, and positive
predictive value were 75, 98.2, and 2.8 percent
respectively for primary invasive cancer.

10. Pelvic ultrsonography
 Specificity was lower forTVUS compared to
multimodal screening, resulting in nine times
as many surgeries performed for theTVUS
compared to the MMS group to detect one
cancer.
Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer,
and stage distribution of detected cancers: results of the prevalence screen of the UK
CollaborativeTrial of Ovarian Cancer Screening (UKCTOCS).
Menon U et al Lancet Oncol. 2009;10(4):327

11. Multimodal screening
 The combination of serum CA 125 and ultra -
sonography, either performed sequentially
(ultrasound only if the CA 125 is elevated) or
concurrently.
 In the UKCTOKS both MMS and USS strategies
had encouraging sensitivity for primary EOC
(89.5% and 75%, respectively).
 PPV was significantly higher in the MMS group
(35.1% versus 2.8% in USS) resulting in lower
rates of repeat testing and surgery .

12.  The MMS has superior sensitivity (88.6% vs 65.8%)
and PPV (21.7% vs 5.8%) compared to the USS arm
for detection of primary EOC.
 Ca-125 is interpreted ROCA is a Bayesian algorithm
that compares the CA125 profile of cases to that of
healthy women and incorporates age-specific
incidence of OC in calculating the risk.
 The closer the individual's profile is to the pattern of
diseased women, the higher the estimated risk

14. The Kentucky study
 Single arm prospective study 37,293 women received
annual ultrasonographic screening between 1987-2011.
 47 invasive EOC and 15 epithelial ovarian tumors of LMP
were detected.
 stage I, 22 (47%) stage II, 11 (23%)
 stage III, 14 (30%) and stage IV, 0 (0%).
 Follow-up varied from 2 months to 20.1 years (mean,
5.8 years)

15. The Kentucky study
 SURVIVAL DATA.
The 5-year survival rate for invasive EOC
detected by screening was:
- Stage I: 95%±4.8%
- Stage II: 77.1%±14.5%;
- Stage III: 76.2%±12.1%.

16. The Kentucky study
Survival data:
 The 5-year survival rate for all women with EOC
detected by screening as well as interval cancers
was 74.8%±6.6% compared with 53.7%±2.3% for
unscreened women with ovarian cancer from the
same institution treated by the same surgical and
chemotherapeutic protocols (P<.001).
 Healthy volunteer effect .
Long-Term Survival ofWomen With Epithelial Ovarian Cancer Detected by
Ultrasonographic Screening van Nagell et al .
Obstetrics & Gynecology :December 2011 -Volume 118 - Issue 6 - p 1212–1221

17. PLCO
 Screening of 30,630 women found 1740 with either
an abnormal CA 125 or ultrasound, and 34 had both .
 RCT with 1 screening strategy :
Ultrasound and CA-125 using a 35 kU/l cut-off
 Lower sensitivity (69.5%) for primary OC/FT
cancer; (only 28% were Stage I/II)
 Nearly one in three women who had a positive
screening test underwent surgery .

18. PLCO
 Among 570 women who had surgery, 29 tumors were found, of
which 20 were invasive (90 percent of these stage III or IV)
 There was no difference in the stage of ovarian cancer, with
advanced disease (stage III or IV) in 77 percent of the cancers in the
intervention group and 78 percent in the usual care group.
 No mortality benefit: 118 ovarian cancer deaths in the screened arm,
100 in the control arm.
 The trial was stopped prior to scheduled completion because the
monitoring board determined futility.

19. Japanese study
 In a randomized controlled trial of 83,000
postmenopausal women in Japan, 42,000 women were
invited to participate in annual screening with pelvic
ultrasound and CA 125.
 No significant difference in the detection of ovarian
cancer, at an average follow-up of 9.2 years, between
patients who received screening (27 cases) and control
patients (32 cases).
 There was a non-significant trend toward earlier-stage
disease in the screened group.Thirty-three surgeries
were performed to detect each case of ovarian cancer.
Mortality data are not yet available.

20. UKCTOCS ( Promising trial)
 The trial randomly assigned 202,638
postmenopausal women aged 50 to 74 years
to no screening, annualTVUS, or multimodal
screening (MMS) .
 Two screening arms (ultrasound) and CA125
followed by ultrasound (multimodal, MMS)
CA125 interpreted using the Risk of Ovarian
Cancer (ROC) algorithm

21.  Superior sensitivity (88.6% vs 65.8%) and PPV
(21.7% vs 5.8%) of MMS compared to the USS
arm for detection of primary invasive epithelial
OC/FT cancers during incidence screening.
 40.3% in the MMS and 51.5% in the USS arm
detected at early stage.
 Mortality data awaited in 2014/2015Mortality
data to be reported in 2015

25. Discussion
 The largest ovarian cancer screening trial ever.
 41,4 % ( 55 of 133 ) of women were detected with stage 1 or 2
disease.
 Compared to single threshold rule , risk algorithm using serial
biomarker measurement doubled the number of screen detected
cancers .
 ROCA detected 86,4 % .
35 : 41,3 %
30 : 48,4 %
22 : 66,5%
For each iEOC detected, four additional women underwent surgery.

26. High risk women
 In a cohort of 888 women carriers of BRCA 1 or 2 mutations
who underwent screening with annual transvaginal
ultrasound and CA 125.
 5 of 10 incident cancers were interval cases diagnosed in
women who had had normal screening results 3 to 10
months previously .
 Eight of the ten cancers were stage III at diagnosis.
Use of a stochastic simulation model to identify an efficient protocol for
ovarian cancer screening.AUUrban N et al Control ClinTrials. 1997;18(3):251.

27. UK Familial Ovarian Cancer
Screening Study (UKFOCSS)1
 Annual screening with CA-125 using a cut-off
andTVS does not detect early stage cancers.
 (UKFOCSS) 3563 women underwent annual
screening with serum CA125 andTVS.
 Only 30.8% of screen-detectedOC/FTCs were
Stage I/II.

28. UKFOCSS 2
 Phase II where annual CA125 screening was replaced by 4-
monthly serum CA125 interpreted using the ROCA.
 ASCO meeting in 2013 :
high sensitivity (67– 100%) for EOC with no interval cancers
reported.
 42% of incident screen-detected OC/FT cancers were
Stage I/II.
 92% of incident screen-detected cancers were completely
cytoreduced compared to 62% on Phase I
 Unsafe alternative to risk reducing surgery.

29. SYNTHESIS OF THE EVIDENCE
 Women at average risk
-Screening for ovarian cancer with CA 125 or
ultrasound is NOT recommended for premenopausal
and postmenopausal women without a family history
of ovarian cancer.
- The predictive value of either test alone (less than 3
percent) yields an unacceptably high rate of false-
positive results and attendant morbidity and costs.

30. SYNTHESIS OF THE EVIDENCE
 High-risk family history
- Women with a suspected hereditary ovarian cancer
syndrome should be referred to a genetic counselor
for consideration of testing for BRCA1 and BRCA2
mutations.
-Women who have not elected risk-reducing surgery,
screening withTVUS plus CA 125 assays every 4
months starting at age 35 years or 5 to 10 years
earlier than the earliest age of first diagnosis of
ovarian cancer in the family.

31. Cancer specific biomarkers
 TP53, BRAF and KRAS are frequently
mutated in OC.
 TP53 mutated in almost allType II cancers
whilst mutations in BRAF and KRAS are more
common in borderline ovarian tumours and
Type I cancers.
Li M, Diehl F, Dressman D, et al. BEAMing up for detection and quantification of
raresequence variants. Nat Methods 2006;3:95–7.

32. Liquid cytology cervical
samples.
 A sequencing method to test for mutations in a
panel of 12 gene.
 It identifies the expected tumor specific mutation.
 Increasing the number of potential gene targets and
improving collection methods could theoretically
allow a more highly enriched sample of cells coming
from the fallopian tube and ovary.
Kinde I, Bettegowda C,WangY, et al. Evaluation of DNA from the
Papanicolaou testto detect ovarian and endometrial cancers. SciTransl Med
2013;5:167ra164.

33. Summary
 Screening average risk women for ovarian
cancer is not recommended.
 2 of 3 randomized trials of screening with
annual CA 125 andTVUS in average-risk
postmenopausal women has shown no
decrease in mortality from ovarian cancer.
 UKCTOCS mortality figures are still awaited.

34.  UKCTOCS mortality figures are still awaited.
 Preliminary data from the trial suggests that
CA125 rise within normal range can be detected
by the ROCA well before any abnormalities are
detected on transvaginal imaging.
 Whether this converts into a mortality impact
will only be known in 2015.

36.  Ca-125 is elevated in 50 to 90 percent of
women with early ovarian cancer, but also
can be elevated in numerous other
conditions.
 Screening with a single measurement of CA
125 alone, either in average- or high-risk
women is not recommended.

37.  TVUS when used as a sole screening
intervention for higher-risk women, has not
been effective in identifying early-stage
cancer.
 TVUS may be more effective when used as
part of MMS, in conjunction with CA 125
interpreted using ROCA.

38.  Periodically screening women with a familial
ovarian cancer syndrome, who have not
undergone prophylactic oophorectomy, with
a combination of CA 125 and transvaginal
ultrasound is recommeded.
 Initiation at age 35 years or 5 to 10 years
earlier than the earliest age of first diagnosis
of ovarian cancer in the family.

39. Thank you